Recent work has shown that spherical nucleic acids (SNAs), structures consisting of linear nucleic acids that are highly oriented and densely packed on the surface of a spherical nanoparticle (NP), exhibit the ability to efficiently enter cells without a transfection agent. (1,2) This is in contrast to free linear nucleic acids, which generally require a cationic moiety to neutralize their negative charge to pass through the cellular membrane. (3) However, these cationic lipids and polymers often display cytotoxic effects at high concentrations and the inability to be degraded biologically. (4-6) SNA-NP conjugates thus provide a unique platform for internalizing large quantities of nucleic acids into cells under mild conditions that can subsequently be used for intracellular detection (7) and gene regulation. (1) Thus far, it has been shown that scavenger receptors mediate the cellular entry of SNAs (8) and cellular uptake is dependent on the density of nucleic acids on the nanoparticle surface. (9) Furthermore, SNA-NP conjugates have a unique set of properties that are advantageous for intracellular applications, including high binding coefficients for DNA that is complementary and RNA, (10) nuclease resistance, (11) and minimal immune response. (12) With respect to cellular internalization and activity, these observations are all based upon the hypothesis that the unique properties of the SNA architecture stem from the oligonucleotide shell and the density and orientation of the nucleic acids that comprise it as opposed to the nanoparticle core. A synthetic route has also been demonstrated for making hollow SNAs by cross-linking oligonucleotides on the surface of gold nanoparticles and subsequently dissolving the gold particle template. Consistent with our hypothesis, these structures are capable of cellular internalization and gene regulation via antisense and RNAi pathways. (13) The hollow structures are attractive, especially if one is concerned about the long-term toxicity of the gold nanoparticle core. (14-16) The disadvantage of the approach is that specialty oligonucleotides capable of cross-linking are required, and at present, they are prohibitively expensive. These observations pose the challenge of identifying other chemical routes to hollow SNA structures that possess similar properties to those derived from gold particles and perhaps offer even greater capabilities.